Phase II: The primary efficacy endpoint is objective tumour response rate as measured by radiological imaging, photography, and/or physical examination performed every other cycle and recorded according to RECIST criteria. [ Time Frame: 3 weeks ] [ Designated as safety issue: No ]

This is a two-part study (Phase I/Phase II). Part I is designed to find the optimal (best) doses of GW572016, docetaxel, and trastuzumab when given together, Part II is designed to evaluate the tumor response rate (shrinkage or lack of growth) in patients receiving all three drugs compared to patients receiving only docetaxel and trastuzumab.

The phase I part of the study will include cohorts of 3 patients to investigate doses of lapatinib (750mg, 1000mg, 1250mg, 1500mg) with 75mg/m2 3- weekly docetaxel plus standard weekly doses of trastuzumab with prophylactic use of growth factors in all patients. Further cohorts may be explored with prophylactic use of growth factors at the doses stipulated in the phase I dose escalation schema

Other Name: GW572016

Drug: Docetaxel, trastuzumab

For Phase II, subjects will be pre-stratified for Eastern Cooperative Oncology Group (ECOG) performance (0 vs. 1; see Appendix 4 ) and site of disease (visceral vs. non-visceral). Subjects will then be randomised in a 2:1 ratio to receive either the triplet regimen or the docetaxel and trastuzumab combination.

Study Arm (s)

Experimental: Phase I

The phase I part of the study will include cohorts of 3 patients to investigate doses of lapatinib (750mg, 1000mg, 1250mg, 1500mg) with 75mg/m2 3- weekly docetaxel plus standard weekly doses of trastuzumab with prophylactic use of growth factors in all patients. Further cohorts may be explored with prophylactic use of growth factors at the doses stipulated in the phase I dose escalation schema

* Includes publications given by the data provider as well as publications
identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.

Recruitment Information

Recruitment Status ICMJE

Active, not recruiting

Enrollment ICMJE

53

Estimated Completion Date

June 2015

Primary Completion Date

June 2010 (final data collection date for primary outcome measure)

Eligibility Criteria ICMJE

Inclusion Criteria:

Subjects must be 18 years of age.

Criteria for female subjects:

Non-child-bearing potential (i.e., women with functioning ovaries who have a current documented tubal ligation or hysterectomy, or women who are post- menopausal);

Child-bearing potential (i.e., women with functioning ovaries and no documented impairment of oviductal or uterine function that would cause sterility.) This category includes women with oligomenorrhoea (severe), women who are perimenopausal, and young women who have begun to menstruate. These subjects must have a negative serum pregnancy test at screening and agree to one of the following:

Complete abstinence from intercourse from 2 weeks prior to administration of the first dose of study medication until 28 days after the final dose of study medication; or

Consistent and correct use of one of the following acceptable methods of birth control:

male partner who is sterile prior to the female subject's entry into the study and is the sole sexual partner for that female subject; implants of levonorgestrel; injectable progestogen; any intrauterine device (IUD) with a documented failure rate of less than 1% per year; oral contraceptives (either combined or progestogen only); or barrier methods, including diaphragm or condom with a spermicide.

Subjects must have an ECOG Performance Status of 0 to 1.

Subjects must have histologically- or cytologically-confirmed invasive breast cancer with Stage IV disease.

Subjects must have measurable lesion(s) according to RECIST criteria for phase II, however for phase I subjects evaluable disease will be allowed (including patients with bone lesion only disease).

Prior to enrolment in the Phase I part of the study, subjects must have documentation of ErbB2 over-expression via IHC3+ or FISH+ testing. Prior to enrolment in the Phase II part of the study, subjects must have ErbB2 over-expression confirmed by a central laboratory,

Subjects with stable CNS metastases or leptomeningeal involvement are eligible only if they are not taking oral steroids or enzyme-inducing anticonvulsants. Subjects with CNS only disease will not be allowed.

Subjects that received prior radiotherapy must have completed radiotherapy treatment at least 4 weeks before enrolment and recovered from all treatment-related toxicities.

Subjects must have new or archived tumour tissue available prior to study entry to evaluate levels of relevant biomarkers.

Subjects must have a cardiac ejection fraction within the institutional range of normal as measured by Multigated Acquisition (MUGA) scan or echocardiogram (ECHO).

Subjects who received a taxane as part of adjuvant or neoadjuvant therapy are eligible if they had progression of their disease more than 6 months after completion of treatment.

Subjects who received prior ErbB inhibitors in the adjuvant setting will be allowed, but a disease-free interval of at least 6 months must be demonstrated after the end of therapy.

Exclusion Criteria:

Subject has peripheral neuropathy of grade 2 or higher;

Subject has had prior systemic therapy (except one line of hormonal therapy) for metastatic disease. Also, any subjects with prior chemotherapy in the adjuvant or neoadjuvant setting with anthracycline or anthracenedione-containing regimens with cumulative doses of ≥360mg/m² of doxorubicin, ≥720mg/m² of epirubicin, or ≥72mg/m² of mitoxantrome;

Subjects with prior systemic investigational drugs within the past 30 days or topical investigational drugs within the past 7 days;

Subjects with a known immediate or delayed hypersensitivity or untoward reaction to docetaxel, trastuzumab, or other related compounds, or to drugs chemically related to lapatinib. These include other anilinoquinazolines, such as gefitinib (Iressa), erlotinib (Tarceva), or other chemically-related compounds.